Aripiprazole, 7-(4-[4-(2,3-dichloropheny)-1-piperazinyl]-butoxy)-3,4-dihydro carbostyril or 7-(4-[4-(2,3-dichloropheny)-1-piperazinyl]-butoxy)-3,4-dihydro-2(1H)-quinolone, is a drug useful as an antipsychotic treatment, as described in U.S. Pat. Nos. 4,737,416 and 5,006,528. The structure of aripiprazole is shown below.

Several polymorphic forms of aripiprazole have been identified. These include six anhydrous polymorphic forms, designated types I to VI, two pseudo polymorphs, a monohydrate and a ½ ethanolate. These polymorphic forms have been disclosed, for example, in Patent Publication Nos. US2004058935 and WO 03/026659. Aripiprazole anhydrate may be used for the formulation of therapeutic treatments, however the hygroscopic nature of these crystals has made them difficult to handle, particularly to prevent exposure to moisture. Upon exposure to water, the anhydrous forms take up water and are converted to a hydrous form or hydrate. The hydrates are however less bioavailable and result in a slower dissolution rate than the anhydrous forms. Recently, WO 03/026659 disclosed various polymorphic forms of aripiprazole anhydrate, including an Anhydrate B form having reduced ygroscopicity, and which was thus more amenable to pharmaceutical processing and formulation. This Anhydrate is prepared via a process in which a hydrous form, Hydrate A, serves as an intermediate. This hydrate is prepared from the milling of what is known as Conventional Hydrate, as is disclosed in WO 03/026659. The Hydrate A is then transformed to Anhydrate B through a heating process.
The Hydrate A, also known herein as aripiprazole monohydrate, though demonstrating usefulness as an intermediate, has a low solubility in water and thus also presents certain processing challenges. The known process of preparing it from Conventional Hydrate by milling has obvious drawbacks in reduced processing efficiency and cost. It is therefore desirable to identify a method of preparing aripiprazole monohydrate suitable for use in the preparation of the anhydrate forms.
Generally, the preparation of particles of pharmaceutical compounds of low aqueous solubility has been addressed, for example, by co-formulation with polymers or other excipients that act as carriers, fillers and/or modifiers. In such modes of preparation, the pharmaceutical compound and the polymer or excipient are co-precipitated from a solvent system in which both are dissolved. Alternatively, the particles may be formed using a solution enhanced dispersions (SEDS) system, in which fine particles of a poorly soluble material are coated with a solubility-enhancing material, first starting with a suspension of particles of the pharmaceutical compound in a solution of the coating material. Such a process is taught in Published PCT Application No. WO 96/00610. Using this method, however, the particles must be prepared beforehand and coated in a separate step.
A method for the preparation of particles of poorly soluble materials using supercritical fluids is disclosed in U.S. Pat. No. 5,851,453 to Hanna et al. (“Hanna”). Hanna describes an apparatus and method for preparing particles by solution enhanced dispersion by supercritical fluid (SEDS). According to Hanna's method, SEDS processing includes controlling the temperature and pressure of a particle formation vessel into which a supercritical fluid and a mixture including a substance that is either in solution or suspension are co-introduced. The combination of the supercritical fluid and the substance-containing mixture results in the substantially simultaneous dispersion and extraction of the substance from the mixture by the supercritical fluid.
While Hanna gives examples of solids that may be used with the process, there is no disclosure of what properties a solid must possess to be prepared with the process. Furthermore, Hanna does not describe a process for the preparation of a crystalline aripiprazole monohydrate.
U.S. Pat. No. 6,461,642 to Bisrat et al. (“Bisrat”) also describes a preparation for particles using a SEDS technique. However, this process is directed toward the preparation of powders for pulmonary administration.
In view of the foregoing discussion and recognition of the problems associated with preparation of pharmaceutical compounds in general, and aripiprazole anhydrates in particular, it would seem desirable to provide a process for the preparation of crystalline aripiprazole monohydrate from unprocessed aripiprazole that provides particles of a size useful for the preparation of an anhydrate form, or for incorporation into pharmaceutical formulations, for example suspensions for intramuscular administration.